tbuckley/cabot-search huggingface dataset:
Phase I/II clinical trial of a helper peptide vaccine plus PD-1 blockade in PD-1 antibody-naïve and PD-1 antibody-experienced patients with melanoma (MEL64)
Authors: Rick D Vavolizza, Gina R Petroni, Ileana S Mauldin, Kimberly A Chianese-Bullock, Walter C Olson, Kelly T Smith, Lynn T Dengel, Kathleen Haden, William W Grosh, Varinder Kaur, Nikole Varhegyi, Elizabeth M Gaughan, Craig L Slingluff
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background A vaccine containing 6 melanoma-associated peptides to stimulate helper T cells (6MHP) is safe, immunogenic, and clinically active. A phase I/II trial was designed to evaluate safety and immunogenicity of 6MHP vaccines plus programmed death 1 (PD-1) blockade. Participants and methods Participants with advanced melanoma received 6MHP vaccines in an incomplete Freund’s adjuvant (6 vaccines over 12 weeks). Pembrolizumab was administered intravenously every 3 weeks. Tumor biopsies at baseline and day 22 were analyzed by multiplex immunohistochemistry. Primary end points were safety (Common Terminology Criteria for Adverse Events V.4.03) and immunogenicity (ex vivo interferon-γ ELISpot assay). Additional end points included changes in the tumor microenvironment (TME) and clinical outcomes. Results Twenty-two eligible participants were treated: 6 naïve to PD-1 antibody (Ab) and 16 PD-1 Ab-experienced. Median follow-up was 24.4 months. Most common treatment-related adverse events (any grade) included injection site reactions, fatigue, anemia, lymphopenia, fever, elevated aspartate aminotransferase, pruritus, and rash. Treatment-related dose-limiting toxicities were observed in 3 (14%) participants, which did not cross the study safety bound. A high durable T cell response (Rsp) to 6MHP was detected in only one participant, but twofold T cell Rsps to 6MHP were detected in 7/22 (32%; 90% CI (16% to 52%)) by week 13. Objective clinical responses were observed in 23% (1 complete response, 4 partial responses), including 4/6 PD-1 Ab-naïve (67%) and 1/16 PD-1 Ab-experienced (6%). Overall survival (OS) was longer for PD-1 Ab-naïve than Ab-experienced participants (HR 6.3 (90% CI (2.1 to 28.7)). In landmark analyses at 13 weeks, OS was also longer for those with T cell Rsps (HR 6.5 (90% CI (2.1 to 29.2)) and for those with objective clinical responses. TME evaluation revealed increased densities of CD8 + T cells, CD20 + B cells, and Tbet + cells by day 22. Conclusions Treatment with the 6MHP vaccine plus pembrolizumab was safe, increased intratumoral lymphocytes, and induced T cell Rsps associated with prolonged OS. The low T cell Rsp rate in PD-1 Ab-experienced participants corroborates prior murine studies that caution against delaying cancer vaccines until after PD-1 blockade. The promising objective response rate and OS in PD-1 Ab-naïve participants support consideration of a larger study in that setting.
After JAK inhibitor failure: to cycle or to switch, that is the question – data from the JAK-pot collaboration of registries
Authors: Manuel Pombo-Suarez, Carlos Sanchez-Piedra, Juan Gómez-Reino, Kim Lauper, Denis Mongin, Florenzo Iannone, Karel Pavelka, Dan C Nordström, Nevsun Inanc, Catalin Codreanu, Kimme L Hyrich, Denis Choquette, Anja Strangfeld, Burkhard F Leeb, Ziga Rotar, Ana Rodrigues, Eirik Klami Kristianslund, Tore K Kvien, Ori Elkayam, Galina Lukina, Sytske Anne Bergstra, Axel Finckh, Delphine Sophie Courvoisier
Journal: Annals of the Rheumatic Diseases (2022)

The expanded therapeutic arsenal in rheumatoid arthritis (RA) raises new clinical questions. The objective of this study is to compare the effectiveness of cycling Janus kinase inhibitors (JAKi) with switching to biologic disease-modifying antirheumatic drug (bDMARD) in patients with RA after failure to the first JAKi.This is a nested cohort study within data pooled from an international collaboration of 17 national registries (JAK-pot collaboration). Data from patients with RA with JAKi treatment failure and who were subsequently treated with either a second JAKi or with a bDMARD were prospectively collected. Differences in drug retention rates after second treatment initiation were assessed by log-rank test and Cox regression analysis adjusting for potential confounders. Change in Clinical Disease Activity Index (CDAI) over time was estimated using a linear regression model, adjusting for confounders.365 cycling and 1635 switching patients were studied. Cyclers were older and received a higher number of previous bDMARDs. Both strategies showed similar observed retention rates after 2 years of follow-up. However, adjusted analysis revealed that cycling was associated with higher retention (p=0.04). Among cyclers, when the first JAKi was discontinued due to an adverse event (AE), it was more likely that the second JAKi would also be stopped due to an AE. Improvement in CDAI over time was similar in both strategies.After failing the first JAKi, cycling JAKi and switching to a bDMARD appear to have similar effectiveness. Caution is advised if an AE was the reason to stop the first JAKi.
Aggressive or Moderate Fluid Resuscitation in Acute Pancreatitis
Authors: Enrique de-Madaria, James L Buxbaum, Patrick Maisonneuve, Ana García García de Paredes, Pedro Zapater, Lucía Guilabert, Alicia Vaillo-Rocamora, Miguel Á Rodríguez-Gandía, Jesús Donate-Ortega, Edgard E Lozada-Hernández, Alan J R Collazo Moreno, Alba Lira-Aguilar, Laura P Llovet, Rajiv Mehta, Raj Tandel, Pablo Navarro, Ana M Sánchez-Pardo, Claudia Sánchez-Marin, Marina Cobreros, Idaira Fernández-Cabrera, Fernando Casals-Seoane, Diego Casas Deza, Eugenia Lauret-Braña, Eva Martí-Marqués, Laura M Camacho-Montaño, Verónica Ubieto, Mikel Ganuza, Federico Bolado
Journal: New England Journal of Medicine (2022)

Early aggressive hydration is widely recommended for the management of acute pancreatitis, but evidence for this practice is limited.
Phase 1 study of C-CAR088, a novel humanized anti-BCMA CAR T-cell therapy in relapsed/refractory multiple myeloma
Authors: Xiaoyan Qu, Gang An, Weiwei Sui, Tingyu Wang, Xian Zhang, Junfang Yang, Yan Zhang, Lu Zhang, Dan Zhu, Jiaqi Huang, Shigui Zhu, Xin Yao, Jing Li, Chengxiao Zheng, Kevin Zhu, Yutian Wei, Xiaoteng Lv, Liping Lan, Yihong Yao, Daobin Zhou, Peihua Lu, Lugui Qiu, Jianyong Li
Journal: Journal for ImmunoTherapy of Cancer (2022)

Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor T-cell (CAR T) therapy showed remarkable efficacy in patients with relapsed or refractory multiple myeloma (RRMM). This phase 1 dose-escalation and expansion study developed C-CAR088, a novel second-generation humanized anti-BCMA CAR T-cell therapy, and assessed the safety and efficacy of three dosages of C-CAR088 in patients with RRMM.
Case 28-2022: A 59-Year-Old Man with Headache and Progressive Neurologic Dysfunction
Authors: David Jayne, John H. Stone, Otto Rapalino, James R. Stone
Journal: New England Journal of Medicine (2022)

A 59-year-old man was evaluated for headache and progressive neurologic dysfunction. Giant-cell arteritis and cranial nerve palsies had been diagnosed previously. Neuroimaging revealed pachymeningitis. A diagnosis was made.
The Duality of Arsenic Metabolism: Impact on Human Health
Authors: Mahmoud A. El-Ghiaty, Ayman O.S. El-Kadi
Journal: The Annual Review of Pharmacology and Toxicology (2022)

Arsenic is a naturally occurring hazardous element that is environmentally ubiquitous in various chemical forms. Upon exposure, the human body initiates an elimination pathway of progressive methylation into relatively less bioreactive and more easily excretable pentavalent methylated forms. Given its association with decreasing the internal burden of arsenic with ensuing attenuation of its related toxicities, biomethylation has been applauded for decades as a pure route of arsenic detoxification. However, the emergence of detectable trivalent species with profound toxicity has opened a long-standing debate regarding whether arsenic methylation is a detoxifying or bioactivating mechanism. In this review, we approach the topic of arsenic metabolism from both perspectives to create a complete picture of its potential role in the mitigation or aggravation of various arsenic-related pathologies.
Leading Oral SERD Shows Prolonged Activity
Journal: Cancer Discovery (2022)

Elacestrant, the leading oral drug candidate designed to degrade the estrogen receptor, continues to show prolonged antitumor activity, according to data presented at the ESMO Congress 2022. But not all oral selective estrogen receptor degraders have demonstrated impressive efficacy. In August, Sanofi announced that it was ending development of amcenestrant after an interim analysis of a pivotal phase III trial found that the study would likely end in failure.
Elicitation of stem-like CD8<sup>+</sup>T cell responses via lymph node-targeted chemoimmunotherapy evokes systemic tumor control
Authors: Margaret P Manspeaker, Meghan J O'Melia, Susan N Thomas
Journal: Journal for ImmunoTherapy of Cancer (2022)

Tumor-draining lymph nodes (TdLNs) are critical in the regulation of local and systemic antitumor T cell immunity and are implicated in coordinating responses to immunomodulatory therapies.Biomaterial nanoparticles that deliver chemotherapeutic drug paclitaxel to TdLNs were leveraged to explore its effects in combination and immune checkpoint blockade (ICB) antibody immunotherapy to determine the benefit of TdLN-directed chemoimmunotherapy on tumor control.Accumulation of immunotherapeutic drugs in combination within TdLNs synergistically enhanced systemic T cell responses that led to improved control of local and disseminated disease and enhanced survival in multiple murine breast tumor models.These findings suggest a previously underappreciated role of secondary lymphoid tissues in mediating effects of chemoimmunotherapy and demonstrate the potential for nanotechnology to unleashing drug synergies via lymph node targeted delivery to elicit improved response of breast and other cancers.
Balance between immunoregulatory B cells and plasma cells drives pancreatic tumor immunity
Authors: Bhalchandra Mirlekar, Yan Wang, Sirui Li, Mi Zhou, Sarah Entwistle, Tristan De Buysscher, Ashley Morrison, Gabriela Herrera, Cameron Harris, Benjamin G. Vincent, Jenny P.- Y. Ting, Naim Rashid, William Y. Kim, Jen Jen Yeh, Yuliya Pylayeva-Gupta
Journal: Cell Reports Medicine (2022)

Plasma cell responses are associated with anti-tumor immunity and favorable response to immunotherapy. B cells can amplify anti-tumor immune responses through antibody production; yet B cells in patients and tumor-bearing mice often fail to support this effector function. We identify dysregulated transcriptional program in B cells that disrupts differentiation of naive B cells into anti-tumor plasma cells. The signaling network contributing to this dysfunction is driven by interleukin (IL) 35 stimulation of a STAT3-PAX5 complex that upregulates the transcriptional regulator BCL6 in naive B cells. Transient inhibition of BCL6 in tumor-educated naive B cells is sufficient to reverse the dysfunction in B cell differentiation, stimulating the intra-tumoral accumulation of plasma cells and effector T cells and rendering pancreatic tumors sensitive to anti-programmed cell death protein 1 (PD-1) blockade. Our findings argue that B cell effector dysfunction in cancer can be due to an active systemic suppression program that can be targeted to synergize with T cell-directed immunotherapy.
Management of Hyperglycemia in Hospitalized, Non–Critically Ill Adults
Authors: Leslie L. Chang, Guillermo E. Umpierrez, Silvio E. Inzucchi
Journal: New England Journal of Medicine (2022)

This interactive feature about management of hyperglycemia in non–critically ill inpatients who had been receiving metformin at home offers a case vignette accompanied by two essays, one supporting continuing metformin in the hospital and the other stopping metformin and initiating insulin therapy.
Acquired semi-squamatization during chemotherapy suggests differentiation as a therapeutic strategy for bladder cancer
Authors: Manli Wang, Xuelan Chen, Ping Tan, Yiyun Wang, Xiangyu Pan, Tianhai Lin, Yong Jiang, Bo Wang, Huan Xu, Yuying Wang, Yucen Yang, Jian Wang, Lei Zhao, Jiapeng Zhang, Ailing Zhong, Yiman Peng, Jiajia Du, Qi Zhang, Jianan Zheng, Jingyao Chen, Siqi Dai, Feifei Na, Zhenghao Lu, Jiaming Liu, Xiaonan Zheng, Lu Yang, Peng Zhang, Ping Han, Qiyong Gong, Qian Zhong, Kai Xiao, Hanshuo Yang, Hongxin Deng, Yinglan Zhao, Hubing Shi, Jianghong Man, Maling Gou, Chengjian Zhao, Lunzhi Dai, Zhihong Xue, Lu Chen, Yuan Wang, Musheng Zeng, Canhua Huang, Qiang Wei, Yuquan Wei, Yu Liu, Chong Chen
Journal: Cancer Cell (2022)

Cisplatin-based chemotherapy remains the primary treatment for unresectable and metastatic muscle-invasive bladder cancers (MIBCs). However, tumors frequently develop chemoresistance. Here, we established a primary and orthotopic MIBC mouse model with gene-edited organoids to recapitulate the full course of chemotherapy in patients. We found that partial squamous differentiation, called semi-squamatization, is associated with acquired chemoresistance in both mice and human MIBCs. Multi-omics analyses showed that cathepsin H (CTSH) is correlated with chemoresistance and semi-squamatization. Cathepsin inhibition by E64 treatment induces full squamous differentiation and pyroptosis, and thus specifically restrains chemoresistant MIBCs. Mechanistically, E64 treatment activates the tumor necrosis factor pathway, which is required for the terminal differentiation and pyroptosis of chemoresistant MIBC cells. Our study revealed that semi-squamatization is a type of lineage plasticity associated with chemoresistance, suggesting that differentiation via targeting of CTSH is a potential therapeutic strategy for the treatment of chemoresistant MIBCs.
PSMG2-controlled proteasome-autophagy balance mediates the tolerance for MEK-targeted therapy in triple-negative breast cancer
Authors: Xueyan Wang, Jing Yu, Xiaowei Liu, Dan Luo, Yanchu Li, Linlin Song, Xian Jiang, Xiaomeng Yin, Yan Wang, Li Chai, Ting Luo, Jing Jing, Hubing Shi
Journal: Cell Reports Medicine (2022)

Although the MAPK pathway is aberrantly activated in triple-negative breast cancers (TNBCs), the clinical outcome of MEK-targeted therapy is still poor. Through a genome-wide CRISPR-Cas9 library screening, we find that inhibition of PSMG2 sensitizes TNBC cells BT549 and MB468 to the MEK inhibitor AZD6244. Mechanistically, PSMG2 knockdown impairs proteasome function, which in turn activates autophagy-mediated PDPK1 degradation. The PDPK1 degradation significantly enhances AZD6244-induced tumor cell growth inhibition by interrupting the negative feedback signals toward the AKT pathway. Consistently, co-targeting proteasomes and MEK with inhibitors synergistically suppresses tumor cell growth. The autophagy inhibitor chloroquine partially relieves the PDPK1 degradation and reverses the growth inhibition induced by combinatorial inhibition of MEK and proteasome. The combination regimen with the proteasome inhibitor MG132 plus AZD6244 synergistically inhibits tumor growth in a 4T1 xenograft mouse model. In summary, our study not only unravels the mechanism of MEK inhibitor resistance but also provides a combinatorial therapeutic strategy for TNBC in clinics.
Targeting <scp>CD38</scp> to Suppress Osteoarthritis Development and Associated Pain After Joint Injury in Mice
Authors: Paulo Gil Alabarse, Liang‐Yu Chen, Patricia Oliveira, Huaping Qin, Ru Liu‐Bryan
Journal: Arthritis & Rheumatology (2022)

This study was undertaken to determine the role of CD38, which can function as an enzyme to degrade NAD+ , in osteoarthritis (OA) development.Human knee cartilage from normal donors and OA donors were examined for CD38 expression. "Gain-of-function," through overexpression of CD38 via transient transfection, and "loss-of-function," through pharmacologic inhibition of CD38, approaches were used to assess the effects of CD38 on intracellular NAD+ :NADH ratio and catabolic activity in chondrocytes. We also initiated joint injury-induced OA by surgical destabilization of the medial meniscus (DMM) in CD38 knockout mice and wild-type (WT; C57BL/6) mice and in WT male mice in the presence or absence of apigenin treatment. Cartilage degradation, synovial inflammation, subchondral bone changes, and pain behavior were evaluated after DMM surgery. We also examined expression of CD38 and the neuropeptide calcitonin gene-related peptide (CGRP) in knee sections from these mice.CD38 expression was up-regulated in human knee OA cartilage and in chondrocytes stimulated with the proinflammatory cytokine interleukin-1β (IL-1β). Overexpression of CD38 in chondrocytes resulted in reduced cellular NAD+ :NADH ratio and augmented catabolic responses to IL-1β. These effects were reversed by pharmacologic inhibition of CD38. Cartilage degradation and synovial inflammation, associated with increased CD38 expression in cartilage and synovium, osteophyte formation and subchondral bone sclerosis, and pain-like behavior linked to increased CGRP expression in the synovium were observed in WT mice after joint injury. Such effects were significantly reduced in mice deficient in CD38 through either genetic knockout or pharmacologic inhibition.CD38 deficiency exerts OA disease-modifying effects. Inhibition of CD38 has the potential to be a novel therapeutic approach for OA treatment.
Genetic Testing Panels in Inherited Cardiac Diseases—Does Size Really Matter?
Authors: Julia Isbister, Luciana Sacilotto, Christopher Semsarian
Journal: JAMA Cardiology (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Cardiology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Cardiology journal
Annealing High Aspect Ratio Microgels into Macroporous 3D Scaffolds Allows for Higher Porosities and Effective Cell Migration
Authors: Alisa C. Suturin, Andreas J. D. Krüger, Kathrin Neidig, Nina Klos, Nina Dolfen, Michelle Bund, Till Gronemann, Rebecca Sebers, Anna Manukanc, Ghazaleh Yazdani, Yonca Kittel, Dirk Rommel, Tamás Haraszti, Jens Köhler, Laura De Laporte
Journal: Advanced Healthcare Materials (2022)

Abstract Growing millimeter‐scaled functional tissue remains a major challenge in the field of tissue engineering. Therefore, microporous annealed particles (MAPs) are emerging as promising porous biomaterials that are formed by assembly of microgel building blocks. To further vary the pore size and increase overall MAP porosity of mechanically stable scaffolds, rod‐shaped microgels with high aspect ratios up to 20 are chemically interlinked into highly porous scaffolds. Polyethylene glycol based microgels (width 10 µm, lengths up to 200 µm) are produced via in‐mold polymerization and covalently interlinked into stable 3D scaffolds via epoxy‐amine chemistry. For the first time, MAP porosities can be enhanced by increasing the microgel aspect ratio (mean pore sizes ranging from 39 to 82 µm, porosities from 65 to 90%). These porosities are significantly higher compared to constructs made from spherical or lower aspect ratio rod‐shaped microgels. Rapid filling of the pores by either murine or primary human fibroblasts is ensured as cells migrate and grow extensively into these scaffolds. Overall, this study demonstrates that highly porous, stable macroporous hydrogels can be achieved with a very low partial volume of synthetic, high aspect ratio microgels, leading to large empty volumes available for cell ingrowth and cell–cell interactions.
Remote ischemic conditioning in septic shock: the RECO-Sepsis randomized clinical trial
Authors: Martin Cour, Kada Klouche, Bertrand Souweine, Jean-Pierre Quenot, Carole Schwebel, Sophie Perinel, Camille Amaz, Marielle Buisson, Michel Ovize, Nathan Mewton, Laurent Argaud, Romain Hernu, Inesse Gragueb-Chebib, Thomas Baudry, Thomas Madelaine, Sonia Machado, Boris Jung, Elizabeth Coupez, Alexandre Lautrette, Auguste Dargent, Nicolas Terzi, Fabrice Zeni, Guillaume Thiery
Journal: Intensive Care Medicine (2022)
Biodegradable and Antioxidant DNA Hydrogel as a Cytokine Delivery System for Diabetic Wound Healing
Authors: Zhenghao Wang, Wei Li, Liping Gou, Ye Zhou, Ge Peng, Jiayi Zhang, Jiaye Liu, Ruoqing Li, Hengfan Ni, Wanli Zhang, Ting Cao, Qi Cao, Hong Su, Yuan‐Ping Han, Nanwei Tong, Xianghui Fu, Erwin Ilegems, Yanrong Lu, Per‐Olof Berggren, Xiaofeng Zheng, Chengshi Wang
Journal: Advanced Healthcare Materials (2022)

Impaired diabetic wound healing is associated with the persistence of chronic inflammation and excessive oxidative stress, which has become one of the most serious clinical challenges. Wound dressings with anti-inflammatory and reactive oxygen species (ROS)-scavenging properties are desirable for diabetic wound treatment. In this study, a shape-adaptable, biodegradable, biocompatible, antioxidant, and immunomodulatory interleukin-33 (IL-33)-cytogel is developed by encapsulating IL-33 into physically cross-linked DNA hydrogels and used as wound dressings to promote diabetic wound healing. The porous microstructures and biodegradable properties of the IL-33-cytogel ensure the local sustained-release of IL-33 in the wound area, where the sustained-release of IL-33 is maintained for at least 7 days. IL-33-cytogel can induce local accumulation of group 2 innate lymphoid cells (ILC2s) and regulatory T cells (Tregs), as well as M1-to-M2 transition at the wound sites. Additionally, the antioxidant and biocompatible characteristics of DNA hydrogels promote the scavenging of intracellular ROS without affecting cell viability. As a result, local inflammation in the diabetic wound area is resolved upon IL-33-cytogel treatment, which is accompanied by improved granulation tissue regeneration and accelerated wound closure. This study demonstrates a promising strategy in tissue engineering and regenerative medicine by incorporating DNA hydrogels and cytokine immunotherapy for promoting diabetic wound healing.